15-Substituted prostanoic acids

ABSTRACT

9-Oxo-15-Substituted prostanoic acids, and intermediates for their preparation and for the preparation of other known prostaglandins are disclosed. The final products have bronchodilatory activity.

CROSS-REFERENCE TO COPENDING APPLICATION

This is a division of application Ser. No. 569,026 filed Apr. 17, 1975,now U.S. Pat. No. 4,022,821 which is a division of application Ser. No.462,006 filed Apr. 18, 1974, now abandoned, which is acontinuation-in-part of copending application Ser. No. 383,007, filedJuly 26, 1973 now U.S. Pat. No. 3,922,302.

BACKGROUND OF THE INVENTION

The prostaglandins are a group of hormone-like substances which may beviewed as derivatives of prostanoic acid. Several prostaglandins arefound widely distributed in mammalian tissue and have been isolated fromthis source. These prostaglandins have been shown to possess a varietyof biological properties such as bronchodilation, the ability to reducegastric secretion, to modify muscle tone, as well as the ability toraise or lower blood pressure.

Various derivatives of prostaglandins have also been synthesized andreported. 9,15-Dihydroxy prost-13-enoic acid and methods of synthesisthereof are disclosed in U.S. Pat. Nos. 3,432,541 and 3,455,992.9-Oxo-15-hydroxy-15-methyl-prostanoic acid, 15-oxo-9-hydroxy-prostanoicacid, and 9,15-dioxo prostanoic acid are disclosed in U.S. Pat. No.3,671,570.

The present invention concerns a number of new intermediates useful inthe synthesis of 9-oxo-15-hydroxy-15-methyl-prostanoic acid as well asnew unsaturated 15-methyl derivatives which are themselves useful. Inaddition 9-oxo-15-hydroxy-15-ethynyl prostanoic acids and newintermediates thereto are included.

SUMMARY OF THE INVENTION

The invention sought to be patented in a first composition aspectresides in the concept of a chemical compound which is prostanoic acidof the structure: ##STR1## wherein R is methyl, A is cis--CH═CH-- and Bis trans--CH═CH--; R is ethynyl, A is --CH₂ --CH₂ -- and B is CH₂ --CH₂--; R is ethynyl, A is --CH₂ --CH₂ -- and B is trans--CH═CH--; or R isethynyl, A is cis--CH═CH-- and B is trans--CH═CH--; and R¹ is hydrogen,alkyl of from 1 to about 6 carbon atoms, alkali metal, or apharmacologically acceptable cation derived from ammonia or a basicamine.

The tangible embodiments of the first composition aspect of theinvention possess the inherent general physical properties of beingclear to yellow oils, or crystalline solids, and when R¹ is hydrogen aresubstantially insoluble in water and are generally soluble in organicsolvents such as ethyl acetate and ether. Examination of the compoundsproduced according to the hereinafter described process reveals, uponinfrared, nuclear magnetic resonance, and mass spectrographic analysis,spectral date supporting the molecular structures herein set forth. Theaforementioned physical characteristics, taken together with the natureof the starting materials, the mode of synthesis, and the elementalanalyses, confirm the structure of the compositions sought to bepatented.

The tangible embodiments of the first composition aspect of theinvention possess the inherent applied use characteristic of exertingbronchodilating effects upon administration to warm-blooded animals asevidenced by pharmacological evaluation according to standard testprocedures.

The invention sought to be patented in a second composition aspectresides in the concept of a chemical compound which is a prostanoic acidof the structure: ##STR2## wherein A is --CH₂ --CH₂ -- and X is ##STR3##

The tangible embodiments of the second composition aspect of theinvention possess the inherent general physical properties of beingclear to yellow oils, are substantially insoluble in water and aregenerally soluble in organic solvents such as ethyl acetate and ether.

Examination of the compounds produced according to the hereinafterdescribed process reveals, upon infrared, nuclear magnetic resonance,and mass spectrographic analysis, spectral data supporting the molecularstructures herein set forth. The aforementioned physicalcharacteristics, taken together with the nature of the startingmaterials, the mode of synthesis, and the elemental analyses, confirmthe structure of the compositions sought to be patented.

The embodiments of the second composition aspect of the inventionpossess the inherent applied use characteristics of being useful asintermediates for the synthesis of other compositions of the inventionhaving bronchodilating activity, and, in addition, those compoundshaving a cis-5-en, a trans-13-ene, a 9-hydroxy group and having in the15-position either a keto group or a hydrogen and hydroxy substituent,or those having hydroxy and methyl substituents at the 15-position areintermediates for the synthesis of 9-oxo15-hydroxy -15-methyl-prostanoicacid.

The invention sought to be patented in its process aspect resides in theconcept of a method of relieving bronchial spasm and facilitatingbreathing in warm-blooded animals which comprises administering to awarm-blooded animal in need thereof an amount sufficient to relievebronchial spasm and facilitate breathing in such warm-blooded animal ofa prostanoic acid of the formula: ##STR4## wherein R is methyl, A iscis--CH═CH-- and B is trans--CH═CH--; R is ethynyl, A is --CH₂ --CH₂ --and B is --CH₂ --CH₂ --; R is ethynyl, A is --CH₂ --CH₂ -- and B istrans--CH═CH--; or R is ethynyl, A is cis--CH═CH-- and B istrans--CH═CH--; and R¹ is hydrogen, alkyl of from 1 to about 6 carbonatoms, alkali metal, or a pharmacologically acceptable cation derivedfrom ammonia or a basic amine.

The invention sought to be patented in a third composition aspectresides in the concept of a chemical compound which is a prostanoic acidof the structure ##STR5##

The tangible embodiments of the third composition aspect of theinvention possess the inherent general physical properties of beingclear to yellow oils, are substantially insoluble in water, and aresoluble in organic solvents such as ethylacetate and ether.

Examination of the compounds produced according to the hereinafterdescribed process reveals, upon infrared, nuclear magnetic resonance andmass spectrographic analysis, spectral data supporting the molecularstructure herein set forth. The aforementioned physical characteristics,taken together with the mode of synthesis, and the elevated analyses,confirm the structure of the compositions sought to be patented. Theembodiments of the third composition aspect of the invention possess theinherent applied use characteristic of being intermediates in thesynthesis of compounds of Formula I wherein R is ethynyl, A iscis--CH═CH--, and B is trans--CH═CH--.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In describing the synthesis of the compositions of the inventionreference will be made to FIGS. 1, 2, and 3 wherein the formulaerepresenting the various embodiments of the invention have been assignedRoman numerals for purposes of identification.

FIG. 1 illustrates the synthesis of a specific embodiment of Formula Inamely:7-(2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-5-oxo-1α-cyclopentyl)-cis-5-heptenoicacid (IX) and the synthesis of specific embodiments of Formula IInamely:7-(5α-hydroxy-2β-[(3R)-3-hydroxy-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid (VI);7-(5β-hydroxy-2β-[(3R)-3-hydroxy-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid (VII);7-(5α-hydroxy-2β-[3-oxo-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid (V);7-(5α-hydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-1.alpha.-cyclopentyl)-cis-5-heptenoicacid (VIII);5α-hydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-1.alpha.-cyclopentane-heptanoicacid (X); and the synthesis of the known compound2β-[(3RS)-3-hydroxy-3-methyl-octyl]-5-oxo-1α-cyclopentaneheptanoic acid(XII).

FIG. 2 illustrates the synthesis of other embodiments of Formula Inamely2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5-oxo-1α-cyclopentaneheptanoic acid (XVI);2β-[(3RS)-3-ethynyl-3-hydroxy-octyl]-5-oxo-1α-cyclopentane heptanoicacid (XXII); and7-(2β-[3-ethynyl-3-hydroxy-trans-1-octenyl]-5-oxo-1α-cyclopentyl)-cis-5-heptenoicacids (XIX); and of other embodiments of Formula II namely:7-(5β-hydroxy-2β-[3-oxo-trans-1-octenyl]-1α-cyclopentylO-cis-5-heptenoicacid (XVII); 2β-[(3RS)-3-ethynyl-3-hydroxyoctyl]-5β-hydroxy-1α-cyclopentane heptanoic acid (XXI);2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentaneheptanoic acid (XV) and7-(2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentyl)-cis-5-heptenoicacid (XVIII).

FIG. 3 illustrates an alternative synthesis of XIX utilizing theembodiments of Formula XXIII, namely7-(7β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-1,4-dioxaspiro[4,4]non-6α-yl)-cis-5-heptenoicacid (XXIII).

The starting materials in the synthesis of the compositions of theinvention, namely 15-epi PGA₂ (III), and PGA₂ (IV) are well-known in theart. For example, 15-epi PGA₂ may be obtained from the coral Plexaurahomomalla by a procedure as described by A. Weinheimer and R. Spragginsin Tetrahedron Letters, 59, 5185 (1969), and PGA₂ may, if desired, beprepared from 15-epi PGA₂ by an epimerization procedure as described byBundy et al. in Annals of the New York Academy of Sciences, 180, 76,(Apr. 30, 1971). Sodium borohydride reduction of either III or IV yieldsa mixture of compounds VI and VII wherein the hydroxyl group at the C-15position will have an orientation corresponding to that of the startingmaterial selected. Compounds VI and VII may, if desired, be separated bychromatography. Oxidation of VI with dichlorodicyanoquinone (DDQ) givesthe enone V. Treatment of V with methyl magnesium bromide gives VIIIwhich may be converted to IX by a Jones oxidation, or hydrogenated usingtris-(triphenylphosphine(rhodium (I) chloride to give X. Jones oxidationof X gives XI which may be hydrogenated using a palladium on charcoalcatalyst to give XII.

If desired, compounds VII may be monohydrogenated usingtris-(triphenyl-phosphine)-rhodium (i) chloride to give compound XIII.Oxidation of XIII using DDQ gives XIV. Reaction of XIV and ethynylmagnesium bromide gives XV. Jones oxidation of XV gives compound XVI.

DDQ oxidation of compound VII gives compound XVII. Reaction of XVII withethynyl magnesium bromide gives XVIII which is converted, if desired, toXIX. Upon chromatography of XIX two products are isolated which are C-15isomers, and which exhibit identical infrared, nuclear magneticresonance, and mass spectra.

Hydrogenation of XVII using a palladium on charcoal catalyst givescompound XX which when treated with ethynyl magnesium bromide isconverted to XXI. Jones oxidation of XXI gives XXII.

It will be obvious to one skilled in the art that compound VII ormixtures of compounds VI and VII may be substituted for compound VI asstarting intermediate in the synthesis of IX and XII and that theintermediates thereto which correspond to V, VIII, and X will have thering-hydroxyl group in a spatial orientation corresponding to that ofthe starting intermediate selected.

Similarly compound VI or mixtures of compound VI and VII may besubstituted for compound VII as starting intermediate in the synthesisof XVI, XIX, and XXII, and the intermediates thereto namely thosecorresponding to XIII, XIV, XV, XVII, XVIII, and XXI will similarly havethe ring-hydroxyl group in a spatial orientation corresponding to thatof the starting intermediate selected.

Jones oxidation of compound VI or VII or mixtures thereof gives7-[2β-(3-oxo-trans-1-octenyl)-5-oxo-1α-cyclopentyl]-cis-5-heptenoic acid(XXIV). If desired, XXIV may be isolated by standard techniques.Chromatography on silica gel is a convenient method. Treatment of XXIVwith ethylene glycol in the presence of an acid catalyst and inertsolvent, while removing the water formed gives7-(7β-[3-oxo-trans-1-octenyl]-1,4-dioxaspiro[4,4]non-6α-yl)cis-5-heptenoicacid (XXV). If desired, XXV may be isolated by standard techniques.Chromatography on silica gel is a convenient method. Ethynylation of XXVgives XXIII. XXIII may, if desired, be separated by standard techniques.Chromatography on silica gel is a convenient method and enables theseparation of C-15 isomers, which are formed by the synthesis reaction.Treatment of XXIII with aqueous acid gives XIX. The orientation of theC-15 isomer of XIX so obtained will correspond to that of XXIII used. Ifdesired, XIX may be isolated by standard techniques. Chromatography onsilica gel is a convenient method.

It will be apparent to those skilled in the art of chemistry that thecarbon atoms on the octane side chain to which hydroxyl substituents areattached are assymetric carbon atoms, and as a consequence thesepositions can be either of two epimeric configurations. The symbol whereused in this specification is to indicate that both possibleconfigurations at each particular position is intended and is includedwithin the scope of the invention.

The esters of formula I (R¹ is alkyl) are prepared by standard methods,such as for example, by treating a solution of the free acids withdiazomethane or other appropriate diazohydrocarbons, such asdiazoethane, 1-diazo-2-ethylpentane, and the like. The alkali metalcarboxylates of the invention can be prepared by mixingstoichiometrically equivalent amounts of the free acids of formula I,preferably in aqueous solution, with solutions of alkali metal bases,such as sodium, potassium, and lithium hydroxides or carbonates, and thelike, then freeze drying the mixture to leave the product as a residue.The amine salts can be prepared by mixing the free acids, preferably insolution, with a solution of the appropriate amine, in water,isopropanol, or the like, and freeze drying the mixture to leave theproduct as a residue.

The term "alkyl of from about 1 to about 6 carbon atoms" when usedherein and in the appended claims includes straight and branched chainhydrocarbon radicals, illustrative members of which are methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl,2,3-dimethylbutyl, and the like. "Alkali metal" includes, for example,sodium, potassium, lithium, and the like. A"pharmacologically-acceptable cation derived from ammonia or a basicamine" contemplates the positively charged ammonium ion and analogousions derived from organic nitrogenous bases strong enough to form suchcations. Bases useful for the purpose of formingpharmacologically-acceptable non-toxic addition salts of such compoundscontaining free carboxyl groups form a class whose limits are readilyunderstood by those skilled in the art. Merely for illustration, theycan be said to comprise, in cationic form, those of the formula:##STR6## wherein R¹, R², and R³, independently, are hydrogen, alkyl offrom about 1 to about 6 carbon atoms, cycloalkyl of from about 3 toabout 6 carbon atoms, monocarbocyclicaryl of about 6 carbon atoms,monocarbocyclicarylalkyl of from about 7 to about 11 carbon atoms,hydroxyalkyl of from about 1 to about 3 carbon atoms, ormono-carbocyclicarylhydroxyalkyl of from about 7 to about 15 carbonatoms, or, when taken together with the nitrogen atom to which they areattached, any two of R¹, R², and R³ form part of a 5 to 6-memberedheterocyclic ring containing carbon, hydrogen, oxygen, or nitrogen, saidheterocyclic rings and said monocarbocyclicaryl groups beingunsubstituted or mono- or dialkyl substituted, said alkyl groupscontaining from about 1 to about 6 carbon atoms. Illustrative thereforeof R groups comprising pharmacologically-acceptable cations derived fromammonia or a basic amine are ammonium, mono-, di-, andtrimmethylammonium, mono-, di- and triethylammonium, mono-, di-, andtripropylammonium (iso and normal), ethyldimethylammonium,benzyldimethylammonium, cyclohexylammonium, benzylammonium,dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium,1-n-butyl-piperidinium, 2-methylpiperidinium,1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium,ethylidiethanolammonium, n-butylmonoethanolammonium,tris(hydroxymethyl)-methylammonium, phenylmonoethanolammonium, and thelike.

In practicing the method of the invention, the instant compositions canbe administered in a variety of dosage forms, the oral route being usedprimarily for maintenance therapy while injectables tend to be moreuseful in acute emergency situations. Inhalation (aerosols and solutionfor nebulizers) seems to be somewhat faster acting than other oral formsbut slower than injectables and this method combines the advantages ofmaintenance and moderately-acute stage therapy in one dosage unit.

The daily dose requirements vary with the particular compositions beingemployed, the severity of the syptoms being presented, and the animalbeing treated. The dosage varies with the size of the animal. With largeanimals (about 70 kg. body weight), by the oral inhalation route, withfor example a hand nebulizer or a pressurized aerosol dispenser the doseis from about 5 micrograms to about 100 micrograms, and preferably fromabout 10 to about 50 micrograms, approximately every 4 hours, or asneeded. By theoral ingestion route, the effective dose is from about 1to about 20 mg., preferably from about 5 to about 15 mg. up to a totalof about 40 mg. per day. By the intravenous route, the ordinarilyeffective dose is from about 50 micrograms to about 300 micrograms,preferably about 200 micrograms per day.

For unit dosages, the active ingredient can be compounded into any ofthe usual oral dosage forms including tablets, capsules and liquidpreparations such as elixirs and suspensions containing variouscoloring, flavoring, stabilizing and flavor masking substances. Forcompounding oral dosage forms the active ingredient can be diluted withvarious tableting materials such as starches of various types, calciumcarbonate, lactose, sucrose and dicalcium phosphate to simplify thetableting and capsulating process. A minor proportion of magnetismstearate is useful as a lubricant. In all cases, of course, theproportion of the active ingredient in said composition will besufficient to impart bronchodilating activity thereto. This will rangeupward from about 0.000 % by weight of active ingredient in saidcomposition.

For administration by the oral inhalation route with conventionalnebulizers or by oxygen aerosolization it is convenient to provide theinstant active ingredient in dilute aqueous solution, preferably atconcentrations of about 1 part of medicament to from about 100 to 200parts by weight of total solution. Entirely conventional additives maybe employed to stabilize these solutions or to provide isotonic media,for example, sodium chloride, sodium citrate, citric acid, sodiumbisulfite, and the like can be employed.

For administration as a self-propelled dosage unit for administering theactive ingredient in aerosol form suitable for inhalation therapy thecomposition can comprise the active ingredient suspended in an inertpropellant (such as a mixture of dichlorodifluoromethane anddichlorotetrafluoroethane) together with a co-solvent, such as ethanol,flavoring materials and stabilizers. Instead of a co-solvent there canalso be used a dispersing agent such as oleyl alcohol. Suitable means toemploy the aerosol inhalation therapy technique are described fully inU.S. Pat. Nos. 2,868,691 and 3,095,355, for example.

The following examples further illustrate the best mode contemplated bythe inventor of making the compositions of the invention.

EXAMPLE 17-(5α-Hydroxy-2β-[(3R)-3-Hydroxy-Trans-1-Octenyl]-1α-Cyclopentyl)-Cis-5-HeptenoicAcid and7-(5β-Hydroxy-2β-[(3R)-3-Hydroxy-Trans-1-Octenyl]-1α-Cyclopentyl)-Cis-5-HeptenoicAcid

An ice-cooled solution of 4.0 g. of7-(2β-[(3R)-3-hdroxy-trans-1-octenyl]-5-oxo-1α-cyclopent-3-enyl)-cis-5-heptenoicacid in 110 ml. of a 10:1 mixture methanol water is treated with 2.2 g.of sodium borohydride, and stirred at 25° for 7 hours. The mixture isconcentrated under vacuum at 40° , the residue diluted with water,acidified with acetic acid and the mixture partitioned with ether. Afterwashing and drying, the extract is evaporated and the residuechromatographed on silica. Elution with 35% ethyl acetate-hexane affordsthe first title product as an oil, λ_(max) ^(film) 2.95, 3.4, 5.8, 7.1,8.1, 8.8, 9.7, 10.3 μ. NMR: δ 5.48 (M, 4, olefinic H), 4.62 (2, OH),4.28 (M, 2, 9 and 15-H) ppm. Mass spectrum: M⁺ at m/e (theory 338),M+--H₂ O at m/e 320.2331 (theory 320.2350).

Further elution with 40% ethyl acetate-hexane gives the second titleproduct as an oil, λ_(max) ^(film) 3.0, 3.4, 5.8, 7.1, 8.1, 9.35, 10.3μ. NMR: δ 5.55 (M, 4, olefinic H), 4.58 (s, OH), 4.05 (M, 2, 9 and 15-H)ppm. Mass spectrum: M⁺ at m/e 338 (theory 338). M⁺ --H₂ O at m/e320.2384 (theory 320.2350).

EXAMPLE 27-[5α-Hydroxy-2β-(3-Oxo-Trans-1-Octenyl)-1α-Cyclopentyl]-Cis-5-HeptenoicAcid

A solution of 3.63 g. of7-(5α-hydroxy-2β-[3R-3-hydroxy-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid in 250 ml. of dioxane is treated with 3.63 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred at 55° for 40hours under nitrogen. The solution is concentrated under vacuum at 40°and the residue chromatographed on silica. Elution with 30% ethylacetate-hexane yields 1.8 g. of the title product as an oil, λ_(max)^(film) 3.0 (shoulder), 3.4, 5.8, 6.0 (shoulder), 6.15 (shoulder), 7.1,8.1, 10.2 μ. UV: λ_(max) ^(EtOH) 232 mμ(ε 12,000). NMR: δ 6.72 (dd, 1,J=5.3 and 15, 13-H), 6.08 (d, 1, J=15, 14-H); 5.40 (M,2,5 and 6-H), 4.25(M, 1, 9-H) ppm. Mass spectrum: QM⁺ at m/e 337 (theory 337), QM⁺ --H₂ Oat m/e 319 (theory 319).

EXAMPLE 37-(5α-Hydroxy-2β-[(3RS)-3-Hydroxy-3-Methyl-Trans-1-Octenyl]-1.alpha.-Cyclopentyl)-Cis-5-HeptenoicAcid

An ice-cooled solution of 1.7 g. of7-[5α-hydroxy-2β-(3-oxo-trans-1-octenyl)-1α-cyclopentyl]-cis-5-heptenoicacid in 150 ml. of tetrahydrofuran is treated with 15 ml. of 3M methylmagnesium bromide in ether dropwise over 10 minutes, under nitrogen.After stirring at 0° for 45 minutes, the mixture is added to ammoniumchloride solution, acidified with acetic acid and extracted with ether.After washing and drying, the extract is evaporated and the residuechromatographed on silica. Elution with 35% ethyl acetate-hexane affords1.07 g. of the title product as an oil, λ_(max) ^(film) 3.0, 3.4, 5.8,8.1, 10.3 μ. NMR: δ 5.42 (M, 4, olefinic H), 5.12 (s, 3, OH), 4.20 (M,1, 9-H), 1.28 (s, 15-CH₃) ppm. Mass spectrum: QM⁺ --H₂ O at m/e 335(theory 335).

EXAMPLE 47-(2β-[(3RS)-3-Hydroxy-3-Methyl-Trans-1-Octenyl]-5-Oxo-1α-Cyclopentyl)-Cis-5-HeptenoicAcid

An ice-cooled solution of 1.02 g. of7-(5α-hydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-1.alpha.-cyclopentyl)-cis-5-heptenoicacid in 80 ml. of acetone is treated dropwise with Jones reagent untilthe orange color persists. After stirring at 0° for 1/2 hour, themixture is treated with 5 ml. of methanol and dilute sodium bicarbonateuntil basic. The mixture is diluted with water, acidified with aceticacid and extracted with ether. After washing and drying, the extract isevaporated and the residue chromatographed on silica. Elution with 30%ethyl acetate-hexane gives 0.12 g. of the title product as an oil,λ_(max) ^(film) 3.0, 3.4, 5.75, 7.1, 8.15, 8.65, 10.3 μ. NMR: δ 6.80 (s,2, OH), 5.72 (M, 2, 13 and 14-H), 5.52 (M, 2, 5 and 6-H), 1.30 (s,15-CH₃) ppm. Mass spectrum: QM⁺ at m/e 351 (theory 351).

EXAMPLE 55α-Hydroxy-2β-[(3RS)-Hydroxy-3-Methyl-Trans-1-Octenyl]-1α-CyclopentaneHeptanoic Acid

A solution of 2.5 g of7-(5α-hydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-1.alpha.-cyclopentyl)-cis-5-heptenoicacid in 35 ml. of 1:1 benzene-ethanol is added to a prehydrogenatedsolution of 0.63 g of tris-(triphenylphosphine) rhodium (I) chloride in115 ml. of 1:1 benzene-ethanol and the mixture hydrogenated at 25° andatmospheric pressure until 1 equivalent of hydrogen is absorbed.Evaporation of the solvent and silica chromatography of the residue with45% ethyl acetate-hexane gives 1.878 g. of the title product as an oil,λ_(max) ^(film) 3.0, 3.5, 5.85, 6.85, 8.95, 10.3 μ. NMR: δ 5.55 (M,2, 13and 14-H), 1.98 (s, 3, OH), 4.32 (M, 1, 9-H) ppm. Mass spectrum: QM⁺--2H₂ O at m/e 319.2636 (theory 319.2636).

EXAMPLE 62β-[(3RS)-3-Hydroxy-3-Methyl-Trans-1-Octenyl]-5-Oxo-1α-CyclopentaneheptanoicAcid

An ice-cooled solution of 1.795 g. of5α-hydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-1-octenyl]-1.alpha.-cyclopentane-heptanoicacid in 120 ml. of acetone is treated dropwise with Jones reagent untilthe orange color persists. After stirring at 0° for 25 minutes, themixture is treated with 10 ml. of methanol and dilute sodium bicarbonateuntil basic. Following dilution with water, the mixture is acidifiedwith acetic acid and extracted with ether. The extract is washed, dried,evaporated and the residue chromatographed on silica. Elution with 30%ethyl acetate-hexane affords 0.33 g. of the title product as an oil,λ_(max) ^(film) 2.95 (shoulder), 3.4, 5.75, 6.8, 8.6, 10.25 μ. NMR: δ6.22 (OH), 5.62 (M, 13 and 14-H), 1.28, 1.28 (15-CH₃) ppm. Massspectrum: QM⁺ --H₂ O at m/e 335 (theory 335).

EXAMPLE 72β-[(3RS)-3-Hydroxy-3-Methyloctyl]-5-Oxo-1α-Cyclopentaneheptanoic Acid

A solution of 0.29 g. of2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]-5-oxo-1α-cyclopentaneheptanoicacid in 20 ml. of ethyl acetate is added to a prehydrogenated mixture of0.09 g. of 10% Pd/C in 10 ml. of ethyl acetate and the mixturehydrogenated at 25% and atmospheric pressure for 16 hours. The mixtureis filtered, evaporated and the residue chromatographed on silica.Elution with 40% ethyl acetate-hexane gives 0.16 g. of the title productas an oil, λ_(max) ^(film) 3.0, 3.4, 5.72, 6.8, 8.65 μ. NMR: 6.02 (s,OH), 1.18 (s, 15--CH₃) ppm. Mass spectrum: M⁺ at m/e 354.2729 (theory354.2768).

EXAMPLE 85β-Hydroxy-2β-[(3R)-3-Hydroxy-Trans-1-Octenyl]-1α-CyclopentaneheptanoicAcid

A solution of 4.4 g. of7-(5β-hydroxy-2β-[(3R)-3-hydroxy-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid in 50 ml. of 1:1 benzene-ethanol is added to a prehydrogenatedsolution of 1.1 g. of tris-(triphenylphosphine) rhodium (I) chloride in200 ml. of 1:1 benzene-ethanol and the mixture hydrogenated at 25° andatmospheric pressure until 1 equivalent of hydrogen is absorbed.Evaporation of the solvents and silica chromatography of the residuewith 40% ethyl acetate-hexane affords 2.7 g. of the title product as anoil, λ_(max) ^(film) 3.05, 3.4, 5.85, 6.8, 8.1, 9.8, 10.3 μ. NMR: δ 5.58(M, 2, 13 and 14-H), 3.95 (M,2,9 and 15-H) ppm. Mass spectrum: M⁺ at m/e340 (theory 340), M⁺ --H₂ O at m/e 322.2493 (theory 322.2507).

EXAMPLE 9 5β-Hydroxy-2β-(3-Oxo-Trans-1-Octenyl)-1α-CyclopentaneHeptanoic Acid

A solution of 2.7 g. of5β-hydroxy-2β-[(3R)-3-hydroxy-trans-1-octenyl]-1α-cyclopentane heptanoicacid in 150 ml. of dioxane is treated with 2.7 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture stirred at 75°for 18 hours under nitrogen. After cooling to 25°, the mixture isfiltered, diluted with ether, filtered again and washed with water. Theether solution is then extracted 4 times with aqueous saturated sodiumbicarbonate and the aqueous extracts acidified with acetic acid andextracted with ether. The other extract is combined with the originalether solutin, evaporated and the residue chromatographed on silica.Elution with 40% ethyl acetae-hexane gives 1.42 g. of the title productas an oil, λ_(max) ^(film) 3.0 (shoulder), 3.4, 5.85, 6.0 (shoulder),6.15 8.4, 9.35, 10.2 μ. UV: λ_(max) ^(EtOH) 230 mμ(ε 13,200). NMR: δ 6.8(dd, 1, J=7.5 and 15, 13-H), 6.0 (d, 1, J=15, 14-H), 3.95 (M, 1, 9-H)ppm. Mass spectrum: QM⁺ at m/e 339 (theory 339).

EXAMPLE 102β-[(3RS)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5β-Hydroxy-1.alpha.-CyclopentaneHeptanoic Acid

A solution of 1.42 g. of5β-hydroxy-2β-(3-oxo-trans-1-octenyl)-1α-cyclopentane heptanoic acid in30 ml. of tetrahydrofuran is added to an ice-cooled solution of ethynylmagnesium bromide (made from 13.3 ml. of 3M methyl magnesium bromide andexcess acetylene) in 170 ml. of tetrahydrofuran and the mixture stirredat 0° for 15 minutes and at 25° for 3 hours. The mixture is diluted withaqueous ammonium chloride solution, acidified with acetic acid andextracted with ether. After washing and drying, the extract isevaporated and the residue chromatographed on silica. Elution with 40%ethyl acetate-hexane affords 1.03 g. of the title product as an oil,λ_(max) ^(film) 3.05, 3.4, 5.8, 9.3, 10.3 μ. NMR: δ 5.95 (dd, 1, J=7.5and 15, 13-H), 5.4 (d, 1, J=15, 14-H), 3.92 (M, 1, 9-H₋,2.58 (s, 1,acetylenic H) ppm. Mass spectrum: QM⁺ at m/e 365 (thoery 365).

EXAMPLE 112β-[(3RS)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5-Oxo-1α-CyclopentaneHeptanoic Acid

An ice-cooled solution of 1.0 g. of2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentaneheptanoicacid in 75 ml. of acetone is treated with Jones reagent (3.9 ml.) over20 minutes until the orange color persists. After stirring at 0° for 1/2hour, under nitrogen, the mixture is treated with 10 ml. of methanol anddilute sodium bicarbonate until basic. Following dilution with water andacidification with acetic acid, the mixture is extracted with ether andthe extract wadhed, dried and evaporated. Silica chromatography of theresidue with 30% ethyl acetatehexane gives 0.27 g. of the title productas an oil, λ_(max) ^(film) 3.05, 3.45, 5.8, 7.1, 8.65, 10.3 μ. NMR: δ5.98 (dd, 1, J=7.5 and 15, 13-H), 5.55 (d, 1, J=15, 14-H),2.60 (s, 1,acetylenic H) ppm. Mass spectrum: QM⁺ at m/e 363 (theory 363 ).

EXAMPLE 127-[5β-Hydroxy-2β-(3-Oxo-Trans-1-Octenyl)-1α-Cyclopentyl]-Cis-5-HeptenoicAcid

A solution of 0.51 g. of7-(5β-hydroxy-2β-[(3R)-3-hydroxy-trans-1-octenyl]-1α-cyclopentyl)-cis-5-heptenoicacid in 40 ml. of dioxane is treated with 0.51 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the mixture stirred at 55°for 24 hours under nitrogen. The mixture is evaporated and the residuechromatographed on silica with 40% ethyl acetate-hexane to obtain 0.58g. of the title product as an oil, λ_(max) ^(film) 3.0 (shoulder), 3.4,5.85, 6.0 (shoulder), 6.15 (shoulder), 8.1, 9.3, 10.2 μ. UV: λ_(max)^(EtOH) 231 mμ (ε 14,050). NMR: δ 6.85 (dd, 1, J=7.5 and 16, 13-H), 6.08(d, 1, J=16, 14-H), 5.50 (M, 2, 5 and 6-H), 4.00 (M, 1, 9-H) ppm. Massspectrum: M⁺ at m/3 336.2299 (theory 336.2299).

EXAMPLE 13 5β-Hydroxy-2β-(3-Oxo-Octyl)-1α-Cyclopentaneheptanoic Acid

A solution of 2.68 g. of7-[5β-hydroxy-2β-(3-oxo-trans-1-octenyl)-1α-cyclopentyl]-cis-5-heptenoicacid in 50 ml. of ethyl acetate is added to a prehydrogenated mixture of0.67 g. of 10% Pd/C in 50 ml. of ethyl acetate and hydrogenated at 25°and atmospheric pressure until 2 equivalents of hydrogen are absorbed.The mixture is filtered, evaporated and the residue chromatographed onsilica. Elution with 35% ethyl acetate-hexane affords 1.96 g. of thetitle product as an oil, λ_(max) ^(film) 3.0 (shoulder), 3.4, 5.8, 6.8,7.05, 8.2 μ. NMR: δ 6.35 (s, 2, OH), 3.95 (m, 1, 9-H), 2.2-2.6 (M, 5,CO-CH) ppm. Mass spectrum: QM⁺ --H₂ O at m/e 323 (theory 323).

EXAMPLE 142β-[(3RS)-3-Ethynyl-3-Hydroxyoctyl]-5β-Hydroxy-1α-CyclopentaneheptanoicAcid

A solution of 1.86 g. of 5β-hydroxy-2β-(3-oxo-octyl)-1α-cyclopentaneheptanoic acid in 30 ml. of tetrahydrofuran is added to a solution ofethynyl magnesium bromide (made from 18.0 ml. of 3M methyl magnesiumbromide in ether and excess acetylene) in 220 ml. of tetrahydrofuran andthe mixture stirred at 25° for 2 hours under nitrogen. Followingdilution with aqueous ammonium chloride solution and acidification withacetic acid, the mixture is extracted with ether. After washing anddrying, the extract is evaporated and the residue chromatographed onsilica. Elution with 40% ethyl acetate-hexane gives 1.54 g. of the titleproduct as an oil, λ_(max) ^(film) 3.05, 4.5, 5.8, 6.8, 9.0, 10.7 μ.NMR: δ 5.32 (s, 3, OH), 3.95 (M, 1, 9-H), 2.48 (s, 1, acetylenic H),2.35 (M, 2,CO--CH) ppm. Mass spectrum: QM⁺ --2H₂ O at m/e 331.2633(theory 331.2336 ).

EXAMPLE 15 2β-[(3RS)-3-Ethynyl-3-Hydroxyoctyl]-5-Oxo-1α-CyclopentaneHeptanoic Acid

An ice-cooled solution of 1.45 g. of2β-[(3RS)-3-ethynyl-3-hydroxyoctyl]-5β-hydroxy-1α-cyclopentaneheptanoicacid in 50 ml. of acetone is treated with Jones reagent (4.0 ml.) untilthe orange color persisted and the mixture stirred at 0° for 1/2 hourunder nitrogen. The mixture is treated with 10 ml. of methanol, dilutesodium bicarbonate until basic and diluted with water. Afteracidification with acetic acid, the mixture is extracted with ether andthe extract washed, dried and evaporated. Silica chromatography of theresidue with 30% ethyl acetate-hexane gives 0.32 g. of the title productas an oil, λ_(max) ^(film) 3.05, 3.4, 4.7 (weak), 5.75, 6.8, 7.05, 8.6μ. NMR: δ 6.02 (M, OH), 2.48 (s,acetylenic H) ppm. Mass spectrum: QM⁺--H₂ O at m/e 347 (theory 347).

EXAMPLE 167-(2β-[(3RS)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5β-Hydroxy-1.alpha.-Cyclopentyl)-Cis-5-HeptenoicAcid

A solution of 9.95 g. of7-[5β-hydroxy-2β-(3-oxo-trans-1-octenyl)-1α-cyclopentyl]-cis-5-heptenoicacid in 20 ml. of tetrahydrofuran is added to a solution of ethynylmagnesium bromide (made from 18.9 ml. of 3M methyl magnesium bromide andexcess acetylene) in 270 ml. of tetrahydrofuran and the mixture stirredat 25° for 1 hour under nitrogen. The mixture is diluted with aqueousammonium chloride solution, acidified with acetic acid and extractedwith ether. Following washing and drying, the extract is evaporated andthe residue chromatographed on silica. Elution with 35% ethylacetate-hexane affords 1.55 g. of the title product as an oil, λ_(max)^(film) 3.05, 3.4, 5.8, 10.25 μ. NMR: δ 6.00 (dd, 1, J=7.5 and 15,13-H), 5.52 (M, 2, 5 and 6-H), 5.48 (d, J=15, 14-H), 4.00 (M, 1, 9-H),2.58 (s, 1, acetylenic H) ppm.

EXAMPLE 177-(2β-[(3R)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5-Oxo-1α-Cyclopentyl)-Cis-5-HeptenoicAcid and7-(2β-[(3S)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5-Oxo-1α-Cyclopentyl)-Cis-5-HeptenoicAcid

an ice-cooled solution of 1.415 g. of7-(2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentyl-cis-5-heptenoicacid in 80 ml. of acetone is treated with Jones reagent until the orangecolor persists and the mixture stirred at 0° for 1/2 hour undernitrogen. The mixture is treated with 10 ml. of methanol, dilute sodiumbicarbonate until basic and diluted with water. Following acidificationwith acetic acid, the mixture is extracted with ether and the extractwashed, dried and evaporated. The resulting residue is chromatographedon silica with 50% ethyl acetate-hexane to obtain 0.11 g. of a firstproduct as an oil, λ_(max) ^(film) 3.05, 3.4, 5.75, 7.05, 8.1, 8.6,10.25 μ. NMR: δ 7.22 (s, 2, OH), 5.3-6.4 (M, 4 olefinic H), 2.60 (s,acetylenic H) ppm. Mass spectrum: M⁺ at m/e 360 (theory 360), M⁺ --C₂ H₂at m/e 334.2143 (theory 334.2193).

Continued elution afforded 0.01 g. of a second product, as an oil, whichexhibits spectra identical to that of the first product. On the basis ofrelative mobility in thin layer chromatography the second product isassigned the 3S configuration and the first product is assigned the 3Rconfiguration.

EXAMPLE 18

Anesthetized (Dial-urethane) guinea pigs were artificially respired at aconstant positive air pressure (Starling miniature pump) and changes intidal air during inspiration were recorded, according to the method ofRosenthale et al., Int. Arch. Pharmacol., 172, 91 (1968). Thebronchoconstrictor agent acetylcholine (ACH) was administered at dosesof 10 to 40 mcg/kg. depending on each animal's sensitivity to thiscompound, and control responses to acetylcholine were thus established.Bronchoconstrictor agents raise the resistance of the lungs to inflationthereby decreasing the tidal air flow.7-(2β-[(3S)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5-oxo-1α-cyclopentyl)-cis-5-heptenoicacid was then administered be aerosol, and the animals were thenchallenged again with acetylcholine, and the degree of inhibition ofbronchoconstriction was thus determined. A minimum of two animals wasused at each dose.

    ______________________________________                                        Results.sup.a                                                                                  Mean % Protection VS                                         Total Aerosol Dose (meg)                                                                       ACH Bronchoconstriction                                      ______________________________________                                        1.5 × 10.sup.-1                                                                              32                                                       10.sup.-3            53                                                       10.sup.-2            79                                                       10.sup.-1            92                                                       ______________________________________                                         .sup.a Minimum of 2 animals per dose.                                    

EXAMPLE 197-[2β-(3-Oxo-Trans-1-Octenyl)-5-Oxo-1α-Cyclopentyl]-Cis-5-Heptenoic Acid

A solution of 20.0 g. of 15-epi-PGA₂ in 500 ml. of methanol and 50 ml.of water is colled in an ice bath and treated with 11.0 g. of sodiumborohydride in portions (some foaming) with stirring. After addition ofsodium borohydride, the ice bath is removed and the mixture stirred at25° for 6 hours. The mixture is acidified with acetic acid and thesolvent removed under vacuum (water aspirator) at 40°. The residue isdiluted with water and extracted thrice with ether. The extract iswashed thrice with brine, dried and evaporated (aspirator/40°) to yield22 g. of oil, a mixture of C-9 alcohols. TLC (silica, 65:15:2Bz:Diox:HAc) shows starting ketone at Rf 45 and alcohol products at Rf42 and 48.

The above crude alcohol mixture is dissolved in 1.5 liters of acetone,cooled in an ice bath and treated with 120 ml. of 1.4M Jones reagent.After stirring at 0° for 40 minutes, the mixture is treated with 50 ml.of methanol to destroy excess Jones reagent, neutralized with dilutesodium bicarbonate solution and acidified with acetic acid. The solventis removed (aspirator/40°) and the residue diluted with water andextracted thrice with ether. The extract is washed thrice with brine,dried and evaporated (aspirator/40°). the residue (24 g.) ischromatographed on 1.2 Kg of silicar CC-4 starting with 15% EtOAc-hexaneand the oily title product (13.4 g.) is eluted with 30% EtOAc-hexane.TLC (silica 65:15:2 Bz:Diox:HAc) Rf 55. UV: λ_(max) ^(95%) EtOH 228 mμ(ε 13,000). λ_(max) ^(film) 3.45, 5.75, 5.9, 6.0, 6.15, 7.1, 8.7, 10.2μ. NMR: δ 10.7 (s,1, OH), 6.86 (dd, 1, J=7.5 and 15, 13-H), 6.2 (d, 1,J=15, 14-H), 5.4 (m, 2, 5 and 6-H) ppm.

Analysis for: C₂₀ H₃₀ O₄ ; Calculated: C; 71.82, H; 9.04. Found: C;72.01, H; 9.00.

EXAMPLE 207-(7β-[3-Oxo-Trans-1-Octenyl]-1,4-Dioxaspiro[4.4]non-6α-yl)-Cis-5-HeptenoicAcid

A solution of 4.8 g. of7-[2β-(3-oxo-trans-1-octenyl)-5-oxo-1α-cyclopentyl]-cis-5-heptenoicacid, 50 ml. of ethylene glycol and 80 mg. of p-toluenesulfonic acid isrefluxed under nitrogen with a Dean Stark water separator for 1.5 hours.The mixture is cooled, diluted with 300 ml. of ether, washed thrice withbrine and dried. The solvent is removed (aspirator/40°) and the residue(5.5 g.) chromatographed on 300 g. of silicar CC-4. the crude product isput on the column with 15% ethyl acetate-hexane, allowed to stand for 4hours and then eluted to obtain the oily title product (3.1 g.) with 20%EtOAc-hexane. TLC (silica 65:15:2 Bz:Diox:HAc) shows starting diketoneat Rf 50, desired C-9 monoketal at Rf 55 and C-9, 15 diketal at Rf 60.UV: λ_(max) ^(95%) EtOH 230 mμ (ε 12,810). λ_(max) ^(film) 3.45, 5.75,5.85, 6.0, 6.15, 8.7, 9.65, 10.2 μ. NMR: δ 10.2 (s, 1, OH), 6.82 (dd, 1,J=7.5 and 16.5, 13-H), 6.1 (d, 1, J=16.5, 14-H), 5.42 (m, 2, 5 and 6-H),3.92 (s, 4, ketal H) ppm. Mass spectrum: M⁺ at m/e 378.2423 (theory378.2405).

EXAMPLE 217-(7β-[(3S)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-1,4-dioxaspiro[4.4]non-6α-yl)-Cis-5-HeptenoicAcid

Dry tetrahydrofuran is saturated at 25° by bubbling acetylene (through 2dry ice-acetone traps and alumina drying tube) through with stirring forapproximately 1/2 hour. A solution of 50 ml. of 3M methyl magnesiumbromide/ether in 50 ml. of dry tetrahydrofuran is added dropwise andstirring continued for 1 hour with acetylene continuously bubblingthrough the mixture. A solution of 9.0 g. of7-(7β-[3-oxo-trans-1-octenyl]-1,4-dioxaspiro[4,4]non-6α-yl)-cis-5-heptenoicacid in 120 ml. of dry tetrahydrofuran is added and the mixture stirredfor 1 hour with acetylene continuously bubbling through the mixture. Themixture is added to ammonium chloride solution, acidified with aceticacid, and extracted thrice with ether. The extract is washed thrice withbrine, dried and evaporated (aspirator/40°). Chromotography of theresidue (11 g.) on 1 Kg of silicar CC-4 with 25% ethyl acetate-hexanefirst gives 3.9 g. of the 15-epi isomer followed by 5.2 g. of thedesired oily title product. TLC (silica 65:15:2 Bz:Diox-HAc) showsstarting ketal of Rf 55, title product at Rf 48. μ_(max) ^(film) 3.0,3.4, 4.7 (weak), 5.75, 8.6, 10.2 μ. NMR: δ 5.3-6.1 (m, 4, olefinic), 3.9(s, 4 ketal H), 2.58 (s, C.tbd.CH)ppm. Mass spectrum: M⁺ at m/3 404.2561(theory 404.2558).

EXAMPLE 227-(2β-[(3S)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5-Oxo-1α-Cyclopentyl)-Cis-5-HeptenoicAcid

A solution of 5.2 g. of7-(7β-[(3S)-3-ethynyl-3-hydroxy-trans-1-octenyl]-1,4-dioxaspiro[4.4]non-6α-yl)-cis-5-heptenoicacid in 150 ml. of acetic acid is treated with 75 ml. of water andstirred at 25°/N₂ /1 hour. The solution is diluted with brine, extractedthrice with ether and the extract washed 5 times with brine, dried andevaporated (aspirator/40°). The crude product (5.4 g.) ischromatographed on 520 g. silicar CC-4 and the title product (3.9 g. ofoil) eluted with 30% EtOAc-hexane. [α]_(D) ²⁵° (-) 58.5 (1% CHCl₃).λ_(max) ^(film) 3.0, 3.35, 5.7, 7.0, 8.55, 10.2μ. NMR: δ 6.1 (dd, 1,J=7.5 and 15, 13-H), 5.65 (d, 1, J=15, 14-H) 5.48 (m, 2, 5 and 6-H),2.65 (s, C.tbd.CH)ppm. Mass spectrum: M⁺ at m/e 360.

The subject matter which the applicant regards as his invention isparticularly pointed out and claimed as follows:
 1. A compound which is7-(2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentyl)-cis-5-heptenoicacid.
 2. A compound which is2β-[(3RS)-3-ethynyl-3-hydroxyoctyl]-5β-hydroxy-1α-cyclopentane heptanoicacid.
 3. A compound which is2β-[(3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl]-5β-hydroxy-1.alpha.-cyclopentaneheptanoic acid.